Clinical features and genetic spectrum in Chinese patients with recessive hereditary spastic paraplegia

Wei, Qiao; Dong, Hai‐Lin; Pan, Li-Ying; Chen, Congxin; Yan, Yang-Tian; Wang, Rou-Min; Li, Hongfu; Liu, Zhijun; Tao, Qing‐Qing; Wu, Zhi‐Ying

doi:10.1186/s40035-019-0157-9

Cited by 27 publications

(32 citation statements)

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“…In the current study, HTS analysis of 240 HSP families identified six additional autosomal-recessive HSP families, with eight patients carrying six homozygous or compound heterozygous variants of CAPN1. Among them, the three homozygous variants (c.182_183insC (p.V64Gfs*103) in Families 1 and 4, c.759+1G>A in Family 3, and c.853C>T (p.R285*) in Family 5) were found to be known truncating mutations, 6,11,21 while the three compound heterozygous variants ((c.1442G>A (p.R481Q) in Family 6, c.1493C>T (p.P498L) in Families 2 and 6, and c.1852C> T (p.R618W) in Family 2) were defined as novel, likely-pathogenic missense mutations. A combined total of 33 rare CAPN1 mutations were detected between our cohort and previously reported cases.…”

Section: Discussionmentioning

confidence: 99%

“…A combined total of 33 rare CAPN1 mutations were detected between our cohort and previously reported cases. 5,6,[11][12][13][14][15][16][17][18][19][20][21][22][23][24] Notably, seven mutations (c.182_183insC, c.759+1G>A, c.853C>T, c.1015C>T, c.1142C>T, c.1176G>A, and c.1534C>T) were shared in ≥2 pedigrees, and in particular the nonsense mutation c.1176G>A (p.W392*) was most prevalent, recorded in four pedigrees.…”

Section: Discussionmentioning

confidence: 99%

“…1A and Supplemental File S2: Figure S2), three of which were previously documented pathogenic homozygous mutations (c.182_183insC (p.V64Gfs*103), c.759+1G>A, and c.853C>T (p.R285*)). 6,11,21 The other three additional compound heterozygous missense variants ((c.1442G A (p.R481Q), c.1493C>T (p.P498L), and c.1852C T (p.R618W)) occurred at extremely low allele frequency (<7 9 10 -5 ) and have not yet been reported. The former two of these mutations were located in the C2L Ca2 +binding domain, while the latter was found in the PEF Ca2 + binding domain of calpain-1 (Fig.…”

Section: Genetic Spectra Of Capn1mentioning

confidence: 99%

“…9 Even though mutations in CAPN1 were initially associated with cerebellar ataxia in dogs and humans, 6,10 as well as in human complicated form HSP presented with any of ataxia, dysarthria and amyotrophy, 5 reports of pure form HSP patients with CAPN1 mutations are increasing. [11][12][13][14][15][16][17][18][19][20][21][22][23][24] Given this broad range of symptoms and contributing factors, it remains an ongoing challenge to find a specific, reliable correlation between genotype and phenotype for this disease complex.…”

Section: Introductionmentioning

confidence: 99%

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Novel CAPN1 mutations extend the phenotypic heterogeneity in combined spastic paraplegia and ataxia

Lai

Chen

et al. 2020

Ann Clin Transl Neurol

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Objective: Recessive mutations in the CAPN1 gene have recently been identified in spastic paraplegia 76 (SPG76), a complex hereditary spastic paraplegia (HSP) that is combined with cerebellar ataxia, resulting in an ataxia-spasticity disease spectrum. This study aims to assess the influence of CAPN1 variants on the occurrence of SPG76 and identify factors potentially contributing to phenotypic heterogeneity. Methods: We screened a cohort of 240 unrelated HSP families for variants in CAPN1 using high-throughput sequencing analysis. We described in detail the clinical and genetic features of the SPG76 patients in our cohort and summarized all reported cases. Results: Six unreported CAPN1-associated families containing eight patients with or without cerebellar ataxia were found in our cohort of HSP cases. These patients carried three previously reported homozygous truncating mutations (p.V64Gfs*103, c.759+1G>A, and p.R285*), and three additional novel compound heterozygous missense mutations (p.R481Q, p.P498L, and p.R618W). Lower limbs spasticity, hyperreflexia, and Babinski signs developed in about 94% of patients, with ataxia developing in 63% of cases. In total, 33 pathogenic mutations were distributed along the three reported functional domains of calpain-1 protein, encoded by CAPN1, with no hotspot region. A comparison of gender distribution between the two groups indicated that female SPG76 patients were significantly more likely to present with complicated HSP than male patients (P = 0.015). Interpretation: Our study supports the clinically heterogeneous inter-and intra-family variability of SPG76 patients, and demonstrates that gender and calpain-1 linker structure may contribute to clinical heterogeneity in SPG76 cases.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Genetic Spectra Of Capn1mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Novel CAPN1 mutations extend the phenotypic heterogeneity in combined spastic paraplegia and ataxia

Lai

Chen

et al. 2020

Ann Clin Transl Neurol

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“…We have recently performed comprehensive genetic investigations in Chinese HSP patients and also found that SPG4 and SPG11 were the most frequent form of AD-HSP and AR-HSP in southeast China, respectively (4,5). However, there are still very few reports on genetic analysis of HSP patients in central-southern China.…”

Section: Introductionmentioning

confidence: 99%

The Investigation of Genetic and Clinical Features in Patients with Hereditary Spastic Paraplegia in Central-Southern China

Wang

Zhang

et al. 2020

Preprint

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Objective Hereditary spastic paraplegias (HSPs) are a clinically and genetically heterogeneous group of neurodegenerative disorders. We describe the genetic and clinical features of a cohort of five HSP families from central-southern China. Methods Using targeted exome-sequencing technology, we investigated the genetic and clinical features in five HSP families. We review the clinical histories of these patients as well as the molecular and functional characterization of the associated gene variants. We also performed functional analyse of an intron variant of SPAST in vitro.Results We identified a known SPAST mutation (p.Pro435Leu) in a family with autosomal dominant HSP (AD-HSP) and four novel variants in three HSP families and a sporadic case. These identified four novel variants include a SPG11 nonsense variant (p.Val1979Ter), two B4GALNT1 variants (p.Ser475Phe and c.1002+2T>G), and a splicing site variant in SPAST (c.1245+5G>A). Minigene analysis of the SPAST splicing variant（c.1245+5G>A）revealed that the mutation resulted in mRNAs with a loss of exon 9. The SPG4 family carrying SPAST c.1245+5G>A exhibited obviously genetic anticipation, with a decreased age at onset and increased severity in successive generations. The proband with p.Val1979Ter variant in SPG11 showed characteristic clinical feature of early-onset, severe spasticity, and corpus callosum atrophy which were highly suggestive of the diagnosis of SPG11-associated HSP. Conclusions Our findings strongly support variable phenotype of B4GALNT1-related SPG26 and also expand the clinical and mutation spectrum of HSP caused by mutations in SPG4, SPG11, and B4GALNT1. These results will help to improve the efficiency of early diagnosis in patients clinically suspected of HSP.

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Δ¹‐Pyrroline‐5‐carboxylate synthetase deficiency: An emergent multifaceted urea cycle‐related disorder

Marco-Marı́n

Escamilla-Honrubia

Llácer

et al. 2020

J of Inher Metab Disea

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The bifunctional homooligomeric enzyme Δ1‐pyrroline‐5‐carboxylate synthetase (P5CS) and its encoding gene ALDH18A1 were associated with disease in 1998. Two siblings who presented paradoxical hyperammonemia (alleviated by protein), mental disability, short stature, cataracts, cutis laxa, and joint laxity, were found to carry biallelic ALDH18A1 mutations. They showed biochemical indications of decreased ornithine/proline synthesis, agreeing with the role of P5CS in the biosynthesis of these amino acids. Of 32 patients reported with this neurocutaneous syndrome, 21 familial ones hosted homozygous or compound heterozygous ALDH18A1 mutations, while 11 sporadic ones carried de novo heterozygous ALDH18A1 mutations. In 2015 to 2016, an upper motor neuron syndrome (spastic paraparesis/paraplegia SPG9) complicated with some traits of the neurocutaneous syndrome, although without report of cutis laxa, joint laxity, or herniae, was associated with monoallelic or biallelic ALDH18A1 mutations with, respectively, dominant and recessive inheritance. Of 50 SPG9 patients reported, 14 and 36 (34/2 familial/sporadic) carried, respectively, biallelic and monoallelic mutations. Thus, two neurocutaneous syndromes (recessive and dominant cutis laxa 3, abbreviated ARCL3A and ADCL3, respectively) and two SPG9 syndromes (recessive SPG9B and dominant SPG9A) are caused by essentially different spectra of ALDH18A1 mutations. On the bases of the clinical data (including our own prior patients' reports), the ALDH18A1 mutations spectra, and our knowledge on the P5CS protein, we conclude that the four syndromes share the same pathogenic mechanisms based on decreased P5CS function. Thus, these syndromes represent a continuum of increasing severity (SPG9A < SPG9B < ADCL3 ≤ ARCL3A) of the same disease, P5CS deficiency, in which the dominant mutations cause loss‐of‐function by dominant‐negative mechanisms.

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Clinical features and genetic spectrum in Chinese patients with recessive hereditary spastic paraplegia

Cited by 27 publications

References 50 publications

Novel CAPN1 mutations extend the phenotypic heterogeneity in combined spastic paraplegia and ataxia

Novel CAPN1 mutations extend the phenotypic heterogeneity in combined spastic paraplegia and ataxia

The Investigation of Genetic and Clinical Features in Patients with Hereditary Spastic Paraplegia in Central-Southern China

Δ¹‐Pyrroline‐5‐carboxylate synthetase deficiency: An emergent multifaceted urea cycle‐related disorder

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Clinical features and genetic spectrum in Chinese patients with recessive hereditary spastic paraplegia

Cited by 27 publications

References 50 publications

Novel CAPN1 mutations extend the phenotypic heterogeneity in combined spastic paraplegia and ataxia

Novel CAPN1 mutations extend the phenotypic heterogeneity in combined spastic paraplegia and ataxia

The Investigation of Genetic and Clinical Features in Patients with Hereditary Spastic Paraplegia in Central-Southern China

Δ1‐Pyrroline‐5‐carboxylate synthetase deficiency: An emergent multifaceted urea cycle‐related disorder

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Δ¹‐Pyrroline‐5‐carboxylate synthetase deficiency: An emergent multifaceted urea cycle‐related disorder